Epilepsy affects 50 million people worldwide, and 2.5 million in the United States alone. Fully 25 percent of those with recurrent seizures cannot be controlled by current medical or surgical treatment, and must resort to high doses of sedating medications or experimental therapy. Even when seizures are controlled, patients bear a significant burden of neurological and medication side effects. We propose to assemble an ensemble of accomplished investigators from the University of Pennsylvania, Georgia Institute of Technology, Children's Hospital of Philadelphia and IntelliMedix, a small start-up company through the GIT and Penn, in an intensive five to ten year effort to create a novel therapy for refractory epilepsy: an implantable closed loop system capable of predicting epileptic seizures prior to electrical and behavioral onset and triggering intervention to abort them before clinical expression. This diverse group of investigators represents multiple disciplines and areas of expertise including bioengineering, computer science, computational modeling of neuronal networks, image processing, clinical adult and pediatric epilepsy, cellular and molecular neuroscience, neurophysiology and neuropharmacology. The work will have three major thrusts: (1) Seizure Prediction: Developing and refining seizure prediction algorithms derived from data obtained from implanted biosensors in adults, children and in animal models of human epilepsy, capable of predicting seizures hours to minutes prior to electrical and clinical onset, (2) Mechanisms of ictogenesis: Unraveling the cellular, molecular, neurophysiologic and neuronal network mechanisms underlying the observed signal changes identified by these algorithms through in-vitro and in-vivo experiments in animals, recordings in human candidates for epilepsy surgery, and modeling these findings via computer simulations in order to refine predictive and intervention strategies, (3) Therapeutics: Developing strategies aimed at specific points in the "ictogenic" process, as discovered above, consisting of electrophysiological and pharmacological interventions to disrupt the cascade of events which lead to seizures, in ways which do not interfere with normal brain function. This work will directly give rise to commercially viable intellectual property including: implantable biosensors, miniaturized biocompatible electrical stimulation and drug infusion hardware, stimulation paradigms, customized pharmacologic agents, customized software/hardware interfaces for signal acquisition, processing and synchronization with algorithms for driving therapeutic interventions. It is hoped that a closed loop seizure prediction and prevention device will be implementable in a 5-10 year period and will significantly improve the quality of life of individuals with epilepsy.